Approximately 14% of men will be diagnosed with Prostate Cancer (PCa). Not only is PCa very prevalent, but as the second leading cause of cancer related deaths in men, it is also very deadly. Many of these deaths result from resistance to androgen ablation therapy, defined as Castration Resistant Prostate Cancer (CRPC). The median survival for men with CRPC is only 19 months, emphasizing the need for further research for novel CRPC therapeutics. Many PCas become resistant to androgen ablation therapy through reactivation of the Androgen Receptor (AR). AR is a transcription factor that translocates into the nucleus after being bound by androgens and promotes transcription of many genes, several of which code for metabolic proteins that regulate lipid and protein biosynthesis. Following androgen ablation therapy, the androgen supply is decreased and growth of the cancer slows down due to decreased AR activity, but cells almost certainly develop resistance through reactivation of AR. We have strong preliminary data suggesting that the cell surface receptor Ron tyrosine kinase is important in activating AR in PCa, leading to resistance to androgen ablation therapy. Previous studies established the Ron receptor as a critical player in PCa. Ron expression levels in PCa correlate with disease severity and loss of Ron signaling in the Transgenic Adenocarcinoma of Mouse Prostate model of PCa severely reduces primary tumor growth. Together, these data demonstrate that Ron is not only highly expressed, but plays a functional role in promoting PCa. In regards to promoting CRPC, it was observed that Ron overexpression was sufficient to drive resistance to androgen ablation therapy by overexpressing Ron in androgen sensitive murine Myc-CaP cells in a murine model of CRPC. Prostate tumors with Ron overexpressing Myc-CaP cells display elevated AR activation and require AR to provide growth in androgen depleted conditions. Further, Ron was shown to activate AR in an epithelial cell specific manner. We also identified enhanced macrophage recruitment in Ron OE Myc-CaP tumors and show mechanistically that macrophage conditioned media induces AR activation in prostate cancer cells, suggesting a non-cell autonomous role for macrophages in promoting Ron mediated castration resistant growth. Therefore, the objective of this proposal is to define the mechanisms by which Ron signaling promotes CRPC. In this proposal we will test the hypothesis that Ron signaling promotes CRPC through activation of AR by both cell intrinsic and extrinsic mechanisms. In aim 1 we will determine the mechanism by which cell intrinsic Ron expression promotes CRPC by examining the ability of Ron to directly and indirectly induce AR activation. Aim 2 will test the function of Ron in regulating macrophage infiltration and activation status. This research may have important clinical implications for the treatment of patients with CRPC by providing the scientific underpinnings for targeting the Ron receptor to combat resistance to androgen ablation therapy.